Isoxazole and isothiazole compounds useful in the treatment of inflammation

ABSTRACT

Compounds of Formula (I), pharmaceutical compositions comprising compounds of Formulae (I a) or (VII) and a method of treating a subject with an inflammatory cytokine-mediated disorder comprising administering to the subject a compound of Formulae (I a) or (VII a). The variables of Formulae (I), (I a), (VII) and (VII a) are described herein.

RELATED APPLICATIONS

This application is the U.S. National Stage of International ApplicationNo. PCT/US2004/032986, filed Oct. 7, 2004, published in English, andclaims the benefit of U.S. Provisional Application No. 60/560,719, filedOct. 7, 2003 and U.S. Provisional Application No. 60/516,027, filed Oct.31, 2003. The entire teachings of the above applications areincorporated herein by reference.

GOVERNMENT SUPPORT

The invention was supported, in whole or in part, by a grantN00178-01-C3058 from DARPA. The Government has certain rights in theinvention.

BACKGROUND OF THE INVENTION

Inflammation is often induced by proinflammatory cytokines, such astumor necrosis factor (TNF), interleukin (IL)-1α, IL-1β, IL-6,platelet-activating factor (PAF), macrophage migration inhibitory factor(MIF), HMGB1 and other compounds. These proinflammatory cytokines areproduced by several different cell types, most importantly immune cells(for example, monocytes, macrophages and neutrophils), contributing tovarious disorders during the early stages of an inflammatory cytokinecascade.

The early pro-inflammatory cytokines (e.g., TNF, IL-1, etc.) mediateinflammation, and induce the late release of high mobility group-1(HMG1) (also known as HMG-1 and HMGB1), a protein that accumulates inserum and mediates delayed lethality and further induction of earlypro-inflammatory cytokines.

Tumor Necrosis Factor (TNF) isoforms α and β are soluble proteinsproduced by monocytes and macrophages in response to endotoxin or otherstimuli. Cells other than monocytes or macrophages also make TNFα. Forexample, human non-monocytic tumor cell lines produce TNFα. (For recentreviews on TNF family, see Lin A, et al., Aging Cell. 2002 December;1(2):112-6 and Baugh J. et al., Curr Opin Drug Discov Devel. 2001September; 4(5):635-50.)

Upon binding to its cognate receptor, TNFα activates both apoptosis andNF-kB-dependent survival pathways. TNF causes pro-inflammatory actionswhich result in tissue injury, such as inducing pro-coagulant activityon vascular endothelial cells, increasing the adherence of neutrophilsand lymphocytes, and stimulating the release of platelet activatingfactor from macrophages, neutrophils and vascular endothelial cells.(Pober, et al., J. Immunol. 136:1680 (1986); Pober, et al., J. Immunol.138:3319 (1987); Camussi, et al., J. Exp. Med 166:1390 (1987)).

TNF is also associated with infections, immune disorders, neoplastic,autoimmune and graft-versus host pathologies. TNF can mediate cachexiain cancer, infectious pathology, and other catabolic states. (Kern, etal., (J. Parent. Enter. Nutr. 12:286-298 (1988)). TNF also plays acentral role in gram-negative sepsis and endotoxic shock. Endotoxinstrongly activates monocyte/macrophage production and secretion of TNFand other cytokines. (Michie, et al., Br. J. Surg. 76:670-671 (1989);Debets, et al., Second Vienna Shock Forum, p.463466 (1989); Simpson, etal., Crit. Care Clin. 5:27-47 (1989); Kornbluth, et al., J. Immunol.137:2585-2591 (1986)).

HMGB1 is a member of a family of DNA-binding proteins termed highmobility group (HMG) and has been implicated as a cytokine mediator ofdelayed lethality in endotoxemia (Wang et al., Science 285: 248-251,1999; WO 00/47104). That work demonstrated that bacterial endotoxin(lipopolysaccharide (LPS)) activates monocytes/macrophages to releaseHMGB1 as a late response to activation, resulting in elevated serumHMGB1 levels that are toxic. Antibodies against HMGB1 prevent lethalityof endotoxin even when antibody administration is delayed until afterthe early cytokine response. (ibid.) HMGB1 has also been implicated inmediating other inflammatory disorders such as endotoxin-induced lungedema, sepsis and hemorrhagic shock. (See, e.g., U.S. Pat. Nos.6,448,223 and 6,468,533.)

There is a need for new therapeutic agents which suppress theproduction, release and/or activity of inflammatory cytokines such asTNF and HMGB1 and which therefore can be used in treatment ofinflammatory disorders.

SUMMARY OF THE INVENTION

It has now been discovered that certain derivatives of isoxazole,isoxazolidine, isothiazole and isothiazolidine compounds inhibitproduction and release of certain proinflammatory cytokines such as TNFand HMGB1 (see Examples 1, 2 and 5). Based on this discovery, methods oftreating a subject with an inflammatory cytokine-mediated disorder aswell as pharmaceutical compositions and compositions of matter thatinclude the anti-inflammatory compounds of the present invention aredisclosed.

In one embodiment, the present invention is a compound of Formula (I) ora pharmaceutically acceptable salt thereof:

Ar₁ and Ar₂ are independently a monocyclic six-member optionallysubstituted heteroaryl group.

A₁ is ═N— or —NR^(a)— and A₂ is O or S; R^(a) is H or C1-C6 alkyl.

R₁ is selected from —H, C1-C6 alkyl, phenyl, C1-C6 haloalkyl, halogen,—OH, —OR^(b), C1-C6 hydroxyalkyl, C1-C6 alkoxyalkyl, —O(C1-C6haloalkyl), —SH, —SR^(b), —NO₂, —CN, —NR^(b)CO₂R^(b), —NR^(b)C(O)R^(b),—CO₂R^(b), —C(O)R^(b), —C(O)N(R^(b))₂, —OC(O)R^(b) and —NR^(b)R^(b).

Each R^(b) is H or a C1-C6 alkyl group.

In another embodiment, the present invention is a pharmaceuticalcomposition comprising a pharmaceutically acceptable carrier or diluentand a compound represented by Formula (I a) or a pharmaceuticallyacceptable salt thereof:

Ar₁, Ar₂, A₁, A₂, R₁ and its substituents are defined above for Formula(I).

In another embodiment, the present invention is a pharmaceuticalcomposition comprising a pharmaceutically acceptable carrier or diluentand a compound represented by Formula (VII) or a pharmaceuticallyacceptable salt thereof:

Ar is an optionally substituted, monocyclic, six-member heteroaryl.

A₁ is ═N— or —NR^(a)— and A₂ is O or S.

R₁ is —H, C1-C6 alkyl, phenyl, C1-C6 haloalkyl, halogen, —OH, —OR^(b),C1-C6 hydroxyalkyl, C1-C6 alkoxyalkyl, —O(C1-C6 haloalkyl), —SH,—SR^(b), —NO₂, —CN, —NR^(b)CO₂R^(b), —NR^(b)C(O)R^(b), —CO₂R^(b),—C(O)R^(b), —C(O)N(R^(b))₂, —OC(O)R^(b) or —NR^(b)R^(b).

Each R^(a) is —H or C1-C6 alkyl and each R^(b) is —H or a C1-C6 alkylgroup.

Ring D is optionally substituted with zero, one or more substituentsother than amide and is not an alkylphenol.

In another embodiment, the present invention is a method of treating asubject with an inflammatory cytokine mediated disorder comprisingadministering to the subject a therapeutically effective amount of acompound represented by Formula (I a) or a pharmaceutically acceptablesalt thereof.

In another embodiment, the present invention is a method of treating asubject with an inflammatory cytokine mediated disorder comprisingadministering to the subject a therapeutically effective amount of acompound represented by Formula (VII a) or a pharmaceutically acceptablesalt thereof:

Ar, A₁, A₂, R₁ and ring D and its substituents are as defined above forFormula (VII).

The present invention offers the advantage of providing individuals inneed of treatment for inflammatory conditions with effectivepharmaceutical agents.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is plot of the concentration of TNF, released by LPS-stimulatedRAW cells, as a function of concentration of the compound of Formula (VIf) in the RAW cell culture. A plot of concentration of TNF as a functionof nicotine concentration is included as a control.

FIG. 2 is a side-by-side comparison of plots representing HMGB-1 releaseby LPS-stimulated RAW cells, as a function of concentration of eitherthe compound of Formula (VI f) or nicotine in the RAW cell culture. Therelease is measured as percentage of LPS-stimulated HMGB-1 released byuntreated cells.

FIG. 3 is a table listing IC₅₀ values for the compounds of Formulae (VIf), (VI b), (XII b), (VI e), (VI g) and (XII a).

FIG. 4 is a table showing the number of mice, by days, protected by thecompound of Formula (VI f) against septic shock induced according to CLPmodel.

FIG. 5 is a side-by-side comparison of plots representing TNF productionby LPS-stimulated human macrophages treated by either the compound ofFormula (VI f), (VI d) or nicotine.

FIG. 6 is a plot of TNFα production by LPS-stimulated RAW cells in thepresence of either the compound of Formula (VI f) alone or incombination with α-bingarotoxin.

DETAILED DESCRIPTION OF THE INVENTION

The present invention encompasses pharmaceutical agents, pharmaceuticalcompositions and methods of treatment of cytokine-mediated inflammatorydisorders, particularly, the disorders mediated by pro-inflammatorycytokines such as tumor necrosis factor (TNF), high mobility groupprotein HMGB1, interleukin (IL)-1α, IL-1β, IL-6, platelet-activatingfactor (PAF) and macrophage migration inhibitory factor (MIF). Thecompounds and methods of the invention are particularly useful fortreatment of inflammatory disorders mediated by TNF-α and HMGB1.

In one embodiment, the present invention is a compound represented byFormula (I) or a pharmaceutically acceptable salt thereof. The variablesof Formula (I) are as described above.

In a preferred embodiment, the compound of Formula (I) is represented byFormulae (II), (III) or (IV):

The variables for Formulae (II) to (IV) are described below.

B₁ through B₅ and D₁ through D₅ are independently N or CR^(c), providedthat from one to three of B₁ through B₅ and from one to three of D₁through D₅ are N. Each R^(c) is independently any suitable substituentas described below for a heteroaryl group. R₁ is as described above forFormula (I).

More preferably, in structural Formulae (II) to (IV), R₁ is —H or aC1-C3 alkyl, optionally substituted with a halogen or a hydroxyl, and/orR^(c) is —H, halogen, —NO₂, —CN, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3hydroxyalkyl, C1-C3 alkoxyalkyl, —N(R^(d))₂, —NR^(d)C(O)R^(d), or—C(O)N(R^(d))₂. R^(d) is H or C1-C3 alkyl.

In a more preferred embodiment, the anti-inflammatory compounds of thepresent invention are represented by Formulae (V a) through (V i):

R′ and R″ are independently —H, halogen, —NO₂, —CN, C1-C3 alkyl, C1-C3haloalkyl, C1-C3 hydroxyalkyl, C1-C3 alkoxyalkyl, —N(R^(d))₂,—NR^(d)C(O)R^(d), or —C(O)N(R^(d))₂. R^(d) is as defined above. Specificexamples of the compounds of the present invention are:

In a particularly preferred embodiment, the compounds are represented byFormula (VI d) or (VI f).

In another embodiment, the present invention is a pharmaceuticalcomposition comprising a pharmaceutically acceptable carrier or diluentand any of the compounds represented by Formulae (I), (I a), (II),(III), (IV), (V a) through (V i) and (VI a) through (V i) orpharmaceutically acceptable salts thereof.

In one embodiment the disclosed invention is a pharmaceuticalcomposition comprising a compound of Formula (I a). Preferably, thecompound is represented by Formula (II a):

where variables B₁ through B₅, D₁ through D₅, A₁, A₂ and R₁ are definedabove for Formula (I).

In another embodiment, the present invention is a pharmaceuticalcomposition comprising a pharmaceutically acceptable carrier or diluentand a compound represented by Formula (VII). The variables of Formula(VII) are as described above.

In preferred embodiments, the compounds of Formula (VII) are representedby Formulae (VIII) and (IX):

The variables of Formulae (VIII) and (IX) are as follows.

A₁, A₂ and R₁ are as defined above for Formnula (VII).

B₁ through B₅ are independently N or CR^(c), provided that from one tothree of B₁ through B₅ are N.

Each R^(c) is independently any suitable substituent as described belowfor a heteroaryl group.

Ring D is optionally substituted with zero, one or more substituent R₂.Each R₂ is independently any suitable substituent described below for anaryl group.

More preferably, the compounds of Formula (VII) are represented byFormulae (X) and (XI a) to (XI c):

where one of B₁ through B₃ is N, n is 0, 1 or 2 and m is 0, 1 or 2.

Preferably, in Formulae (VIII) to (XI a) through (XI c) R^(c) is —H,halogen, —NO₂, —CN, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 hydroxyalkyl,C1-C3 alkoxyalkyl, —N(R^(d))₂, —NR^(d)C(O)R^(d), or —C(O)N(R^(d))₂ andR₂ is —H, halogen, —NO₂, —CN, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3hydroxyalkyl or C1-C3 alkoxyalkyl. R^(d) is H or C1-C3 alkyl.

Specific examples of the compounds suitable for using in pharmaceuticalcompositions of the present invention are

In one embodiment, the compounds of Formula (VII a), suitable for usingin the methods of the present invention, are represented by Formula(VIII a):

where B₁ through B₅ and the substituents thereof are defined above forFormula (VIII).

In another embodiment, the compounds suitable for use in the methods ofthe present invention are represented by Formulae (I), (I a), (II), (IIa) (III), (IV), (V a) to (V i), (VI a) to (VI i), (VII), (VII a),(VIII), (IX), (X), (XI a) through (XI c), (XII a) and (XII b) as definedabove.

The term “heteroaryl”, as used herein, refers to aromatic groupscontaining one or more heteroatoms (O, S, or N). A heteroaryl group ofthe present invention is a monocyclic six-member group. The heteroarylgroups of this invention can also include ring systems substituted withone or more oxo moieties. Examples of heteroaryl groups include, but arenot limited to, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl,pyridazinyl, pyridazinyl and triazinyl.

Suitable substituents on a heteroaryl group (including heteroaryl groupsrepresented by Ar, Ar₁ and Ar₂) are those that do not substantiallyinterfere with the pharmaceutical activity of the disclosed compound. Aheteroaryl may have one or more substituents, which can be identical ordifferent. Examples of suitable substituents for a substitutable carbonatom in a heteroaryl group include —H, C1-C6 alkyl, halogen, C1-C6haloalkyl, —R^(o), —OH, —OR^(o), —O(C1-C6 haloalkyl), —SH, —SR^(o),—NO₂, —CN, —NH₂, —NHCO₂R^(o), —NHC(O)H, —NHC(O)R^(o), —NR^(o)C(O)R^(o),—CO₂H, —CO₂R^(o), —C(O)H, —C(O)R^(o), —C(O)NHR^(o), —C(O)N(R^(o))₂,—OC(O)R^(o), —S(O)₂R^(o), —SO₂NH₂, —S(O)R^(o), —NHSO₂R^(o), or a C1-C6alkyl group substituted with R^(o), —OH, —OR^(o), —SH, —SR^(o), —NO₂,—CN, —NHCO₂R^(o), —NHC(O)H, —NHC(O)R^(o), —CO₂H, —CO₂R^(o), —C(O)H,—C(O)R^(o), —C(O)NHR^(o), —OC(O)R^(o), —S(O)₂R^(o), —SO₂NH₂, —S(O)R^(o)or —NHSO₂R^(o). R^(o) is independently, C1-C6 alkyl, aryl or heteroarylgroup and wherein the aryl or heteroaryl group represented by R^(o) isoptionally substituted with one or more halogen, methyl or methoxygroups.

The term “aryl”, as used herein, refers to a carbocyclic aromatic group.Examples of aryl groups include, but are not limited to phenyl andnaphthyl.

A substituted aryl group can have one or more substituents which can bethe same or different. Suitable substituents for a substituted arylgroup, including ring D, typically represented herein as “R₂”, are asdefined above for a heteroaryls, provided that the substituents on ringD are other than amide and that ring D is not an alkylphenol. As usedherein, the term “amide” refers to a —C(O)NHR^(o) group, where R^(o) isdefined above for heteroaryl groups. As used herein, the term“alkylphenol” refers to a six-member monocyclic aryl substituted withone hydroxyl groups and one or more alkyls. Examples of suitablesubstituents for an aryl include —H, halogen, C1-C6 haloalkyl, —R^(o),—OH, —OR^(o), —O(C1-C6 haloalkyl), —SH, —SR^(o), —NO₂, —CN, —NHCO₂R^(o),—NHC(O)H, —NHC(O)R^(o), —CO₂H, —CO₂R^(o), —C(O)H, —C(O)R^(o),—OC(O)R^(o), —S(O)₂R^(o), —SO₂NH₂, —S(O)R^(o), —NHSO₂R^(o), or a C1-C6alkyl group substituted with R^(o), —OH, —OR^(o), —SH, —SR^(o), —NO₂,—CN, —NHCO₂R^(o), —NHC(O)H, —NHC(O)R^(o), —CO₂H, —CO₂R^(o), —C(O)H,—C(O)R^(o), —C(O)NHR^(o), —OC(O)R^(o), —S(O)₂R^(o), —SO₂NH₂, —S(O)R^(o)or —NHSO₂R^(o). R^(o) is as defined above for heteroaryl groups.

The term “alkyl”, as used herein, unless otherwise indicated, includesstraight, branched or cyclic saturated monovalent hydrocarbon radicals,typically C1-C10, preferably C1-C6. Examples of alkyl groups include,but are not limited to, methyl, ethyl, propyl, isopropyl, and t-butyl.

The term “haloalkyl”, as used herein, includes an alkyl substituted withone or more F, Cl, Br, or I, wherein the alkyl is defined above.

The terms “alkoxy”, as used herein, means an “alkyl-O—” group, whereinalkyl, is defined above.

Pharmaceutically acceptable salts of the anti-inflammatory compoundsdisclosed herein can be used to practice the present invention. As usedherein, a “pharmaceutically acceptable salt” of the disclosed compoundis an ionic bond-containing product of reacting a compound of theinvention with either an acid or a base, suitable for administering to asubject. For example, an acid salt of a compound containing an amine orother basic group can be obtained by reacting the compound with asuitable organic or inorganic acid, such as hydrogen chloride, hydrogenbromide, acetic acid, perchloric acid and the like. Other examples ofsuch salts include hydrochlorides, hydrobromides, sulfates,methanesulfonates, nitrates, maleates, acetates, citrates, fumarates,tartrates (e.g. (+)-tartrates, (−)-tartrates or mixtures thereofincluding racemic mixtures), succinates, benzoates and salts with aminoacids such as glutamic acid. Salts can also be formed with suitableorganic bases when the compound comprises an acid functional group suchas —COOH or —SO₃H. Such bases suitable for the formation of apharmaceutically acceptable base addition salts with compounds of thepresent invention include organic bases that are nontoxic and strongenough to react with the acid functional group. Such organic bases arewell known in the art and include amino acids such as arginine andlysine, mono-, di-, and triethanolamine, choline, mono-, di-, andtrialkylamine, such as methylamine, dimethylamine, and trimethylamine,guanidine, N-benzylphenethylamine, N-methylglucosamine,N-methylpiperazine, morpholine, ethylendiamine,tris(hydroxymethyl)aminomethane and the like.

As used herein, a “pharmaceutical composition” is a formulationcomprising the disclosed compounds and a pharmaceutically acceptablediluent or carrier, in a form suitable for administration to a subject.The pharmaceutical composition can be in bulk or in unit dosage form.The unit dosage form can be in any of a variety of forms, including, forexample, a capsule, an IV bag, a tablet, a single pump on an aerosolinhaler, or a vial. The quantity of active ingredient (i.e., aformulation of the disclosed compound or salts thereof) in a unit doseof composition is an effective amount and may be varied according to theparticular treatment involved. It may be appreciated that it may benecessary to make routine variations to the dosage depending on the ageand condition of the patient. The dosage will also depend on the routeof administration. A variety of routes are contemplated, includingtopical, oral, pulmonary, rectal, vaginal, parenternal, includingtransdermal, subcutaneous, intravenous, intramuscular, intraperitonealand intranasal.

The compounds described herein, and the pharmaceutically acceptablesalts thereof can be used in pharmaceutical preparations in combinationwith a pharmaceutically acceptable carrier or diluent. Suitablepharmaceutically acceptable carriers include inert solid fillers ordiluents and sterile aqueous or organic solutions. The compounds will bepresent in such pharmaceutical compositions in amounts sufficient toprovide the desired dosage amount in the range described herein.Techniques for formulation and administration of the compounds of theinstant invention can be found in Remington: the Science and Practice ofPharmacy, 19^(th) edition, Mack Publishing Co., Easton, Pa. (1995).

As used herein, a “subject” includes mammals, e.g., humans, companionanimals (e.g., dogs, cats, birds and the like), farm animals (e.g.,cows, sheep, pigs, horses, fowl and the like) and laboratory animals(e.g., rats, mice, guinea pigs and the like). In a preferred embodimentof the disclosed methods, the subject is human.

As used herein, a “therapeutically effective amount” of a compound ofthe disclosed invention is the quantity which, when administered to asubject in need of treatment, improves the prognosis of the subject,e.g., delays the onset of and/or reduces the severity of one or more ofthe subject's symptoms associated with a fungal infection. The amount ofthe disclosed compound to be administered to a subject will depend onthe particular disease, the mode of administration, and thecharacteristics of the subject, such as general health, other diseases,age, sex, genotype, body weight and tolerance to drugs. The skilledartisan will be able to determine appropriate dosages depending on theseand other factors. Effective amounts of the disclosed compoundstypically range between about 0.1 mg/kg body weight per day and about1000 mg/kg body weight per day, and preferably between 1 mg/kg bodyweight per day and 100 mg/kg body weight per day.

The present invention is directed to treating disorders mediated bypro-inflammatory cytokines such as, for example, TNF-α or HMGB-1.Non-limiting examples of disorders that can be treated using compounds,pharmaceutical compositions and methods of the present invention includeappendicitis, peptic, gastric or duodenal ulcers, peritonitis,pancreatitis, ulcerative, pseudomembranous, acute or ischemic colitis,diverticulitis, epiglottitis, achalasia, cholangitis, cholecystitis,hepatitis, Crohn's disease, enteritis, Whipple's disease, asthma,allergy, anaphylactic shock, immune complex disease, organ ischemia,reperfusion injury, organ necrosis, hay fever, sepsis, septicemia,endotoxic shock, cachexia, hyperpyrexia, eosinophilic granuloma,granulomatosis, sarcoidosis, septic abortion, epididymitis, vaginitis,prostatitis, urethritis, bronchitis, emphysema, rhinitis, cysticfibrosis, pneumonitis, pneumoultramicroscopic silicovolcanoconiosis,alvealitis, bronchiolitis, pharyngitis, pleurisy, sinusitis, influenza,respiratory syncytial virus infection, herpes infection, HIV infection,hepatitis B virus infection, hepatitis C virus infection, disseminatedbacteremia, Dengue fever, candidiasis, malaria, filariasis, amebiasis,hydatid cysts, bums, dermatitis, dermatomyositis, sunburn, urticaria,warts, wheals, vasulitis, angiitis, endocarditis, arteritis,atherosclerosis, thrombophlebitis, pericarditis, myocarditis, myocardialischemia, periarteritis nodosa, rheumatic fever, Alzheimer's disease,coeliac disease, congestive heart failure, adult respiratory distresssyndrome, meningitis, encephalitis, multiple sclerosis, cerebralinfarction, cerebral embolism, Guillame-Barre syndrome, neuritis,neuralgia, spinal cord injury, paralysis, uveitis, arthritides,arthralgias, osteomyelitis, fasciitis, Paget's disease, gout,periodontal disease, rheumatoid arthritis, synovitis, myasthenia gravis,thryoiditis, systemic lupus erythematosus, Goodpasture's syndrome,Behcets's syndrome, allograft rejection, graft-versus-host disease, TypeI diabetes, ankylosing spondylitis, Berger's disease, Type I diabetes,ankylosing spondylitis, Retier's syndrome, or Hodgkins disease. In morepreferred embodiments, the condition is appendicitis, peptic, gastric orduodenal ulcers, peritonitis, pancreatitis, ulcerative,pseudomembranous, acute or ischemic colitis, hepatitis, Crohn's disease,asthma, allergy, anaphylactic shock, organ ischemia, reperfusion injury,organ necrosis, hay fever, sepsis, septicemia, endotoxic shock,cachexia, septic abortion, disseminated bacteremia, bums, Alzheimer'sdisease, coeliac disease, congestive heart failure, adult respiratorydistress syndrome, cerebral infarction, cerebral embolism, spinal cordinjury, paralysis, allograft rejection and graft-versus-host disease.

Preferably, the disorder is peritonitis, pancreatitis, ulcerativecolitis, Crohn's disease, asthma, organ ischemia, reperfusion ischemia,sepsis, cachexia, bums, myocardial ischemia, adult respiratory distresssyndrome, multiple sclerosis, rheumatoid arthritis, systemic lupuserythematous, chronic obstructive pulmonary disease, psoriasis, Behcet'ssyndrome, allograft rejection or graft-versus-host disease. Even morepreferably, the disorder is sepsis.

The disclosed compounds can also be co-administered with one or moreadditional agents such as antibiotics, other anti-inflammatories (e.g.ibuprofen, prednisone (corticosteroid) or pentoxifylline), anti-fungals,(e.g. Amphotericin B, Fluconazole, Ketoconazol, and Itraconazol)steroids, decongestants, bronchodialators, and the like. The disclosedcompounds can also be co-administered with anti-TNF agents (e.g.infliximab, etanercept, adalimumab, CDP870, CDP571, Lenercept andThalidomide). The formulation may also contain preserving agents,solubilizing agents, chemical buffers, surfactants, emulsifiers,colorants, odorants and sweeteners. The compounds of the presentinvention may be co-administered with one or more additional agentsseparately or in the same formulation.

The excipient included with the compounds of the pharmaceuticalcompositions of the invention is chosen based on the expected route ofadministration of the composition in therapeutic applications. The routeof administration of the composition depends on the condition to betreated. For example, intravenous injection may be preferred fortreatment of a systemic disorder such as endotoxic shock, and oraladministration may be preferred to treat a gastrointestinal disordersuch as a gastric ulcer. The route of administration and the dosage ofthe composition to be administered can be determined by the skilledartisan without undue experimentation in conjunction with standarddose-response studies. Relevant circumstances to be considered in makingthose determinations include the condition or conditions to be treated,the choice of composition to be administered, the age, weight, andresponse of the individual patient, and the severity of the patient'ssymptoms. Thus, depending on the condition, the antibody composition canbe administered orally, parenterally, intranasally, vaginally, rectally,lingually, sublingually, bucally, intrabuccally and transdermally to thepatient.

Accordingly, compositions designed for oral, lingual, sublingual, buccaland intrabuccal administration can be made without undue experimentationby means well known in the art, for example, with an inert diluent orwith an edible carrier. The compositions may be enclosed in gelatincapsules or compressed into tablets. For the purpose of oral therapeuticadministration, the pharmaceutical compositions of the present inventionmay be incorporated with excipients and used in the form of tablets,troches, capsules, elixirs, suspensions, syrups, wafers, chewing gumsand the like.

Tablets, pills, capsules, troches and the like may also contain binders,recipients, disintegrating agent, lubricants, sweetening agents, andflavoring agents. Some examples of binders include microcrystallinecellulose, gum tragacanth or gelatin. Examples of excipients includestarch or lactose. Some examples of disintegrating agents includealginic acid, corn starch and the like. Examples of lubricants includemagnesium stearate or potassium stearate. An example of a glidant iscolloidal silicon dioxide. Some examples of sweetening agents includesucrose, saccharin and the like. Examples of flavoring agents includepeppermint, methyl salicylate, orange flavoring and the like. Materialsused in preparing these various compositions should be pharmaceuticallypure and non-toxic in the amounts used.

Various other materials may be present as coatings or to modify thephysical form of the dosage unit. For instance, tablets may be coatedwith shellac, sugar or both. A syrup or elixir may contain, in additionto the active ingredient, sucrose as a sweetening agent, methyl andpropylparabens as preservatives, a dye and a flavoring such as cherry ororange flavor, and the like.

For vaginal administration, a pharmaceutical composition may bepresented as pessaries, tampons, creams, gels, pastes, foams or spray.

The present invention includes nasally administering to the mammal atherapeutically effective amount of the composition. As used herein,nasally administering or nasal administration includes administering thecomposition to the mucous membranes of the nasal passage or nasal cavityof the patient. As used herein, pharmaceutical compositions for nasaladministration of a composition include therapeutically effectiveamounts of the agonist prepared by well-known methods to beadministered, for example, as a nasal spray, nasal drop, suspension,gel, ointment, cream or powder. Administration of the composition mayalso take place using a nasal tampon or nasal sponge.

For topical administration, suitable formulations may includebiocompatible oil, wax, gel, powder, polymer, or other liquid or solidcarriers. Such formulations may be administered by applying directly toaffected tissues, for example, a liquid formulation to treat infectionof conjunctival tissue can be administered dropwise to the subject'seye, or a cream formulation can be administer to a wound site.

The compositions of the present invention can be administeredparenterally such as, for example, by intravenous, intramuscular,intrathecal or subcutaneous injection. Parenteral administration can beaccomplished by incorporating the antibody compositions of the presentinvention into a solution or suspension. Such solutions or suspensionsmay also include sterile diluents such as water for injection, salinesolution, fixed oils, polyethylene glycols, glycerine, propylene glycolor other synthetic solvents. Parenteral formulations may also includeantibacterial agents such as, for example, benzyl alcohol or methylparabens, antioxidants such as, for example, ascorbic acid or sodiumbisulfite and chelating agents such as EDTA. Buffers such as acetates,citrates or phosphates and agents for the adjustment of tonicity such assodium chloride or dextrose may also be added. The parenteralpreparation can be enclosed in ampules, disposable syringes or multipledose vials made of glass or plastic.

Rectal administration includes administering the pharmaceuticalcompositions into the rectum or large intestine. This can beaccomplished using suppositories or enemas. Suppository formulations caneasily be made by methods known in the art. For example, suppositoryformulations can be prepared by heating glycerin to about 120° C.,dissolving the pharmaceutical composition in the glycerin, mixing theheated glycerin after which purified water may be added, and pouring thehot mixture into a suppository mold.

Transdermal administration includes percutaneous absorption of thecomposition through the skin. Transdermal formulations include patches,ointments, creams, gels, salves and the like.

In addition to the usual meaning of administering the formulationsdescribed herein to any part, tissue or organ whose primary function isgas exchange with the external environment, for purposes of the presentinvention, “pulmonary” will also mean to include a tissue or cavity thatis contingent to the respiratory tract, in particular, the sinuses. Forpulmonary administration, an aerosol formulation containing the activeagent, a manual pump spray, nebulizer or pressurized metered-doseinhaler as well as dry powder formulations are contemplated. Suitableformulations of this type can also include other agents, such asantistatic agents, to maintain the disclosed compounds as effectiveaerosols.

A drug delivery device for delivering aerosols comprises a suitableaerosol canister with a metering valve containing a pharmaceuticalaerosol formulation as described and an actuator housing adapted to holdthe canister and allow for drug delivery. The canister in the drugdelivery device has a head space representing greater than about 15% ofthe total volume of the canister. Often, the polymer intended forpulmonary administration is dissolved, suspended or emulsified in amixture of a solvent, surfactant and propellant. The mixture ismaintained under pressure in a canister that has been sealed with ametering valve.

Synthesis of the Compounds of the Invention

The compounds of the present invention can be synthesized according tothe following synthetic scheme:

Ar^(a) and Ar^(b) are each independently 6-member substituted orunsubstituted heteroaryl or aryl group as defined above (includingvariables Ar₁, Ar₂, Ar and ring D). This procedure is based on themethod of isoxazoline synthesis found in Wityak et al., J. Med. Chem.(1997) 40:50-60, incorporated herein by reference.

In particular, compounds (VI f), (VI d) and (XII a) can be preparedaccording to the schemes (2), (3) and (4), respectively.

1) Compound (VI f):

A stirring solution of 3-pyridinecarboxaldehyde oxime (3.00 g, 24.6mmol) and 4-vinylpyridine (8.0 mL, 75 mmol) in THF (60 mL) was chilledby an ice bath. To this solution, a 5% solution of NaOCl (95 mL) wasadded slowly by an addition funnel. When the addition was complete, theice bath was removed and the reaction mixture was allowed to warm toroom temperature. The reaction was quenched with 5% citric acid. Etherwas added to the reaction mixture was separated from the aqueous layer.

The aqueous layer was again extracted with ether, and the combined etherlayers were dried with MgSO4 and concentrated on the roto-evaporator.The crude product was loaded onto a silica column and eluted with 0, 10,20, and 30% EtOAc/heptane. The isoxazoline came off the column in the20-30% regime as a ˜95% spectroscopically (1H NMR) pure solid (1.32 g,23.9%). The compound was crystallized from EtOAc/heptane.

2) Compound (VI d):

A stirring solution of 3-pyridinecarboxaldehyde oxime (3.00 g, 24.6mmol) and 2-vinylpyridine (75 mmol) in THF (60 mL) was chilled by an icebath. To this solution, a 5% solution of NaOCl (95 mL) was added slowlyby an addition funnel. When the addition was complete, the ice bath wasremoved and the reaction mixture was allowed to warm to roomtemperature. The reaction was quenched with 5% citric acid. Ether wasadded to the reaction mixture and was separated from the aqueous layer.

The aqueous layer was again extracted with ether, and the combined etherlayers were dried with MgSO4 and concentrated on the roto-evaporator.The crude product was loaded onto a silica column and eluted with 0, 10,20, and 30% EtOAc/heptane. The isoxazoline came off the column in the20-30% regime as a ˜95% spectroscopically (1H NMR) pure solid 1.53 g,27.7%). The compound was crystallized from EtOAc/heptane.

3) Compound (XII a):

A stirring solution of 4-pyridinecarboxaldehyde oxime (3.00 g, 24.6mmol) and Styrene (75 mmol) in THF (60 mL) was chilled by an ice bath.To this solution, a 5% solution of NaOCl (95 mL) was added slowly by anaddition funnel. When the addition was complete, the ice bath wasremoved and the reaction mixture was allowed to warm to roomtemperature. The reaction was quenched with 5% citric acid. Ether wasadded to the reaction mixture and was separated from the aqueous layer.

The aqueous layer was again extracted with ether, and the combined etherlayers were dried with MgSO4 and concentrated on the roto-evaporator.The crude product was loaded onto a silica column and eluted with 0, 10,20, and 30% EtOAc/heptane. The isoxazoline came off the column in the10-20% regime as a >95% spectroscopically (1H NMR) pure solid (2.1 g,38%). The compound was crystallized from EtOAc/heptane.

Other compounds of the invention can be prepared with these methodsusing the appropriate starting materials. In some instances, where thestarting materials have substituent groups, it may be necessary to useprotecting groups. Suitable protecting groups are known to the one ofordinary skill in the art and are found, for example, in Green and Wuts,“Protective Groups in Organic Synthesis”, John Wiley and Sons (1991),the entire relevant teaching of which are incorporated herein byreference.

EXEMPLIFICATION

The practice of the present invention will employ, unless otherwiseindicated, conventional techniques of cell culture, molecular biology,microbiology, cell biology, and immunology, which are well within theskill of the art. Such techniques are fully explained in the literature.See, e.g., Sambrook et al., 1989, “Molecular Cloning: A LaboratoryManual”, Cold Spring Harbor Laboratory Press; Ausubel et al. (1995),“Short Protocols in Molecular Biology”, John Wiley and Sons; Methods inEnzymology (several volumes); Methods in Cell Biology (several volumes),and Methods in Molecular Biology (several volumes).

Example 1 Compound of Formula (VIf) Suppresses TNF Release fromLPS-Stimulated RAW Cells in a Dose-Dependent Manner

Experiments were performed to determine the effect of compound (VI f) onthe proinflammatory activity of TNFα. Murine RAW 264.7 macrophage-likecells (American Type Tissue Culture Collection, Rockville, Md., USA)were grown under DMEM supplemented with 10% fetal bovine serum,penicillin and streptomycin. The cells were seeded in 24-well tissueculture plates in Opti-MEM 1 medium and used at 90% confluence. Thecells were treated with either compound (VI f) or nicotine (Sigma) at 0,0.001, 0.01, 0.1, 1.0, 10 or 100 μM. Five minutes after the addition ofcompound (VI f) or nicotine, the cells were treated with LPS (500ng/ml). Supernatants were collected after 4 hours and TNF concentrationwas measured by mouse ELISA kit (R&D) Systems Inc., Minneapolis, Minn.).

The results are shown in FIG. 1, which clearly shows that compound (VIf) inhibited TNFα production in a dose-dependent manner. The efficacy ofcompound (VI f) is comparable to or better than that of the nicotinecontrol.

Example 2 Compound of Formula (VIf) Suppresses HMGB-1 Release fromLPS-Stimulated RAW Cells in a Dose-Dependent Manner

Experiments were performed to determine the effect of compound (VI f) onthe proinflammatory effect of HMGB-1. Murine RAW 264.7 macrophage-likecells were grown under DMEM supplemented with 10% fetal bovine serum and1% glutamine. When the cells were 70-80% confluent, the medium wasreplaced by serum-free Opti-MEM I medium. Compound (VI f) was added at0, 0.01, 0.1, 1 or 10 μM or nicotine was added at 0, 0.1, 1, 10 and 100μM. Five minutes after the addition of compound (VI f) or nicotine, thecultures were treated with LPS (500 ng/ml). Culture medium was collectedafter 24 hours. The culture medium was concentrated with a Centricon™ 10filter, then analyzed by western blot using anti-HMGB1 polyclonalantisera and standard methods. The results are presented as percentstimulation of LPS treatment alone.

The results are shown in FIG. 2, which clearly shows that compound (VIf) inhibited HMGB1 production in a dose-dependent manner. The efficacyof compound (VI f) is comparable to or better then that of nicotinecontrol.

Example 3 Compounds of the Invention Exhibit Low IC₅₀ for TNFα Release

Experiments were performed to determine the concentration of severalcompounds of the present invention at which TNFα release was inhibitedby 50% (IC₅₀).

Using murine RAW 264.7 macrophage-like cells and the protocol describedin Example 1, IC₅₀ of compounds (VI f), (VI b), (XII b), (VI e), (VI g)and (XII a) have been measured. The results are summarized in FIG. 3. Ascan be seen from FIG. 3, four out of six compounds tested exhibit IC₅₀values comparable or better than nicotine.

Example 4 Compound (VI f) Protects Mice from Septic Shock in CLP Model

Cecal Ligation and Puncture (CLP) was performed as described in Fink andHeard, J. of Surg. Res. 49:186-196 (1990), Wichman el al., Crit. CareMed. 26:2078-2086 (1998) and Remick et al., Shock 4:89-95 (1995).Briefly, Balb/c mice were anesthetized with 75 mg/kg Ketamine (FortDodge, Fort Dodge, Iowa) and 20 mg/kg of xylazine (Bohringer Ingelheim,St. Joseph, Mo.) intramuscularly. A midline incision was performed, andthe cecum was isolated. A 6-0 prolene suture ligature was placed at alevel 5.0 mm from the cecal tip away from the ileocecal valve.

The ligated cecal stump was then punctured once with a 22-gauge needle,without direct extrusion of stool. The cecum was then placed back intoits normal intra-abdominal position. The abdomen was then closed with arunning suture of 6-0 prolene in two layers, peritoneum and fasciaseparately to prevent leakage of fluid. All animals were resuscitatedwith a normal saline solution administered sub-cutaneously at 20 ml/kgof body weight. Each mouse received a subcutaneous injection of imipenem(0.5 mg/mouse) (Primaxin, Merck & Co., Inc., West Point, Pa.) 30 minutesafter the surgery. Animals were then allowed to recuperate. Mice wereadministered 2 mg/kg compound (VI f) intraperitoneally twice daily for 3days beginning 24 hours after surgery. Mortality was recorded for up to2 weeks after the procedure to ensure no late mortalities had occurred.

The results are presented in FIG. 4, which shows the number of survivinganimals following treatment either by compound (VI f) or an “empty”carrier solution. As can be seen, only two mice died in the compound (VIf)-treated group as compared with six in the untreated control. By day5, only one treated mouse died compared to six in the control group.These results demonstrate that compound (VI f) improved survival ofseptic mice.

Example 5 Compounds (VI d) and (VI f) Inhibit TNFα Production inLPS-Stimulated Macrophages

Human macrophage cultures were prepared as follows. Buffy coats werecollected from the blood of healthy individual donors to the Long IslandBlood Bank Services (Melville, N.Y.). Primary blood mononuclear cellswere isolated by density-gradient centrifugation through Ficoll/Hypaque(Pharmacia, N.J.), suspended (8×10⁶ cells/ml) in RPMI 1640 mediumsupplemented with 10% heat inactivated human serum (Gemini Bio-Products,Inc., Calabasas, Calif.), and seeded in flasks (PRIMARIA; Beckton andDickinson Labware, Franklin Lakes, N.J.). After incubation for 2 hoursat 37° C., adherent cells were washed extensively, treated briefly with10 mM EDTA, detached, resuspended (10⁶ cells/ml) in RPMI medium (10%human serum), supplemented with human macrophage colony stimulatingfactor (MCSF; Sigma Chemical Co., St. Louis, Mo.; 2 ng/ml), and seededonto 24-well tissue culture plates (PRIMARIA; Falcon) (10.sup.6cells/well). Cells were allowed to differentiate for 7 days in thepresence of MCSF. On day 7 the cells were washed 3 times with 1×Dulbecco's phosphate buffered saline (PBS, GibcoBRL, Life Technologies,Rockville, Md.), fresh medium devoid of MCSF was added, and experimentsperformed as indicated.

Primary human macrophage cultures were established by incubating humanperipheral blood mononuclear cells in the presence of macrophage colonystimulating factor (MCSF; Sigma Chemical Co., St. Louis, Mo.). Thesecells were used in experiments to determine the effects of the compoundsof the present invention on TNF levels in macrophage culturesconditioned by exposure to LPS for 4 hours. In those experiments,compounds (VI d) and (VI f) as well as control (nicotine; Sigma ChemicalCo., St. Louis, Mo.) was added to human macrophage cultures at theindicated concentrations (FIG. 5). LPS was added five minutes later (100ng/ml), and conditioned supernatants collected after 4 hours ofstimulation for subsequent analysis by TNF enzyme-linked immunosorbentassay (ELISA). All the experimental conditions were performed intriplicate. Data from nine separate macrophage preparations are shown asMean+/−SEM; n=9.

As can be seen from FIG. 5, compounds (VI d) and (VI f) inhibited TNFrelease in a dose dependent manner with efficacy comparable to or betterthan that of the control.

Example 6 α-Bungarotoxin Overrides Inhibitory Effect of Compound (VI f)on TNFα Release

Experiments were performed to determine whether the inhibitory effect ofthe compound (VI f) on proinflammatory cytokine TNFα can be overriddenby addition of α-bungarotoxin, an antagonist that binds to a subset ofcholinergic receptors including the nicotinic α7 receptor (Lindstrom,1995; Leonard et al, 2001).

Murine RAW 264.7 macrophage-like cells were subjected to the protocol asdescribed in Example 1. The cells were treated with α-bungarotoxin atthe indicated concentration before treatment with compound (VI f).

As shown in FIG. 6, addition of α-bungarotoxin partially abrogated theinhibitory effect of compound (VI f) on LPS-mediated TNFα release, whichdemonstrates that this inhibition is at least partially dependent on anα-bungarotoxin sensitive receptor on the RAW 264.7 cells.

Example 7 Compound (VIf) Reduces Local Inflammation in a SchwartzmanReaction Model

The localized Shwartzman reaction was performed as previously described(C. Sunderkotter, S. Seeliger, F. Schonlau, J. Roth, R. Hallmann, T. A.Luger, C. Sorg, and G. Kolde. 2001. Different pathways leading tocutaneous leukocytoclastic vasculitits in mice. Exp Dermatol10:391-404.). Briefly, female BALB/c mice (22-26g, Taconic) wereinjected with saline or Compound VIf (i.p., at the indicated doses), andthen injected s.c. into the pinnae of the ear wit 20 μg LPS (preparatorydose). One day later, mice (4 per group) were injected either withvehicle (saline) or CAP (i.p., at the indicated doses) 15 min prior tochallenge with LPS (150 μg, i.p.) To generate a localized vasculiticreaction. Five hours later, mice were sacrificed by CO₂ asphyxiation,and the ears were excised and cut in half longitudinally. Ears wereflash frozen in liquid nitrogen and stored at −80° C. Each experimentwas repeated twice.

Ear sections (5μ) from the Shwartzman Reaction were stained using VCAM-1and E-selectin antibodies, according to the manufacturer'srecommendations (BD Biosciences), followed by anti-mouse gG-HRP, anddeveloped with DAB substrate. After immunostaining, slides werecounterstained with H&E, dehydrated, and mounted with permount. Forenumeration of positive staining, three fields per section (threesections per sample) were assessed at 200× magnification and scored asthe average number (+SD) of VCAM-1 or E-selectin positivecapillaries/vessels. Representative slides were photographed at 100×.

By these methods, it was determined that Compound VIf reduced E-selectinand VCAM-1 protein expression by the endothelium when compared tovehicle-treated animals. These results indicate that Compound VIf isprotective in an animal model of local inflammation.

Example 8 Compound (VIf) Reduces Inflammation in a Carrageenan Air PouchModel

The carrageenan air pouch model was performed as previously described(Garcia-Ramallo, et al., J. Immunol. 169:6467 (2002)). Briefly, femaleSwiss Webster mice weighing 26-33 g (Taconic) were used. To generatedorsal air pouches, mice were anesthetized (ketamine/xylazine) on day 0and 6 ml of sterile air was injected s.c. to form a cavity on thedorsum. Three days later, 3 ml of air was injected into the cavity. Onday 6, animals received either vehicle (saline) or Compound VIf dilutedin saline (i.p., at the indicated concentrations) and then 15 minuteslater, 1 ml-1% carrageenan was injected into the pre-formed air pouch.

The animals were sacrificed by CO2 asphyxiation 6 hr post carrageenan;and the cellular infiltrate and fluid exudates were collected aspreviously described (Garcia-Ramallo, et al., J. Immunol. 169:6467(2002)). TNF, PGE2, MCP-1 (monocyte chemoattractant protein-1), MIP-2(macrophage inflammatory protein-2), MIP-1 α (macrophage inflammatoryprotein-α) and MIP-1 (macropphage inflammatory protein-1β) levels in thepouch fluids were determiend by ELISA. The collected cells (RBC-free)were analzyed by flow cytometry to determine cell number by calibratedcounting using a previously described method (Bleul, et al., J Exp Med184:1101 (1996)). Each experiment as repeated at least twice. Macrophageinflammatory protein-1α and -1β (MIP-1α and MIP-1β) were analyzed byELISA as previously described (Sherry, et al., J. Inflamm. 45:85(1995)).

Pouch TNF levels peak 2 h post carrageenan challenge and then decline tobaseline between 24-48 h post carrageenan. Compound VIf (12 mg/kg)reduced TNF levels by 40% as compared to vehicle-treated controls(100±7% control vs. 60±11%). Neutrophils and monocytes, the predominantinflammatory cells within the pouch, express chemokine receptors thatmediate their recruitment by specific chemokines (MIP-2 and MCP-1,respectively). Compound VIf (12 mg/kg) significantly reduced the pouchfluid levels of MCP-1 by 20% and 30%, respectively. By contrast, MIP-2,MIP-1α, MIP-1β levels were only slightly decreased by CAP treatments.

These results indicate that Compound VIf is protective in an animalmodel of local inflammation.

While this invention has been particularly shown and described withreferences to preferred embodiments thereof, it will be understood bythose skilled in the art that various changes in form and details may bemade therein without departing from the scope of the inventionencompassed by the appended claims.

1. A compound of Formula (I) or a pharmaceutically acceptable saltthereof:

wherein: Ar₁ and Ar₂ are independently a monocyclic six-memberoptionally substituted heteroaryl group; A₁ is ═N— or —NR^(a)— and A₂ isO or S; R^(a) is H or C1-C6 alkyl; R₁ is selected from —H, C1-C6 alkyl,phenyl, C1-C6 haloalkyl, halogen, —OH, —OR^(b), C1-C6 hydroxyalkyl,C1-C6 alkoxyalkyl, —O(C1-C6 haloalkyl), —SH, —SR^(b), —NO₂, —CN,—NR^(b)CO₂R^(b), —NR^(b)C(O)R^(b), —CO₂R^(b), —C(O)R^(b),—C(O)N(R^(b))₂, —OC(O)R^(b) and —NR^(b)R^(b); and each R^(b) is H or aC1-C6 alkyl group.
 2. The compound of claim 1 represented by Formula(II):

wherein: B₁ through B₅ and D₁ through D₅ are independently N or CR^(c),provided that from one to three of B₁ through B₅ and from one to threeof D₁ through D₅ are N; each R^(c) is independently —H, C1-C6 alkyl,halogen, C1-C6 haloalkyl, —R^(o), —OH, —OR^(o), —O(C1-C6 haloalkyl),—SH, —SR^(o), —NO₂, —CN, —NHCO₂R^(o), —NHC(O)H, —NHC(O)R^(o), —CO₂H,—CO₂R^(o), —C(O)H, —C(O)R^(o), —C(O)NHR^(o), —OC(O)R^(o), —S(O)₂R^(o),—SO₂NH₂, —S(O)R^(o), —NHSO₂R^(o), —N(R^(o))₂, —NR^(o)C(O)R^(o), or—C(O)N(R^(o))₂ or a C1-C6 alkyl group substituted with R^(o), —OH,—OR^(o), —SH, —SR^(o), —NO₂, —CN, —NHCO₂R^(o), —NHC(O)H, —NHC(O)R^(o),—CO₂H, —CO₂R^(o), —C(O)H, —C(O)R^(o), —C(O)NHR^(o), —OC(O)R^(o),—S(O)₂R^(o), —SO₂NH₂, —S(O)R^(o), —NHSO₂R^(o); and R^(o) isindependently, C1-C6 alkyl, aryl or heteroaryl group and wherein thearyl or heteroaryl group represented by R^(o) is optionally substitutedwith one or more halogen, methyl or methoxy groups.
 3. The compound ofclaim 2 wherein the compound is represented by Formula (III):


4. The compound of claim 3 wherein the compound is represented byFormula (IV):

wherein one of B₁ through B₃ and one of D₁ through D₃ are N.
 5. Thecompound of claim 4 wherein R₁ is —H or a C1-C3 alkyl optionallysubstituted with a halogen or a hydroxyl.
 6. The compound of claim 5wherein R^(c) is —H, halogen, —NO₂, —CN, C1-C3 alkyl, C1-C3 haloalkyl,C1-C3 hydroxyalkyl, C1-C3 alkoxyalkyl, —N(R^(d))₂, —NR^(d)C(O)R^(d), or—C(O)N(R^(d))₂; and each R^(d) is H or a C1-C3 alkyl group.
 7. Thecompound of claim 6 selected from the group consisting of:

wherein: R′ and R″ are independently —H, halogen, —NO₂, —CN, C1-C3alkyl, C1-C3 haloalkyl, C1-C3 hydroxyalkyl, C1-C3 alkoxyalkyl,—N(R^(d))₂, —NR^(d)C(O)R^(d), or —C(O)N(R^(d))₂.
 8. The compound ofclaim 7 selected from the group consisting of:


9. The compound of claim 8 represented by Formula (VId):


10. The compound of claim 8 represented by Formula (VIf):


11. A pharmaceutical composition comprising a pharmaceuticallyacceptable carrier or diluent and a compound represented by Formula (Ia) or a pharmaceutically acceptable salt thereof:

wherein: Ar₁ and Ar₂ are independently a monocyclic six-memberoptionally substituted heteroaryl group; A₁ is ═N— or —NR^(a)— and A₂ isO or S; R^(a) is H or C1-C6 alkyl; R₁ is selected from —H, C1-C6 alkyl,phenyl, C1-C6 haloalkyl, halogen, —OH, —OR^(b), C1-C6 hydroxyalkyl,C1-C6 alkoxyalkyl, —O(C1-C6 haloalkyl), —SH, —SR^(b), —NO₂, —CN,—NR^(b)CO₂R^(b), —NR^(b)C(O)R^(b), —CO₂R^(b), —C(O)R^(b),—C(O)N(R^(b))₂, —OC(O)R^(b) and —NR^(b)R^(b); and each R^(b) is H or aC1-C6 alkyl group.
 12. The composition of claim 11 wherein the compoundis represented by Formula (II a):

wherein: B₁ through B₅ and D₁ through D₅ are independently N or CR^(c),provided that from one to three of B₁ through B₅ and from one to threeof D₁ through D₅ are N; each R^(c) is independently —H, C1-C6 alkyl,halogen, C1-C6 haloalkyl, —R^(o), —OH, —OR^(o), —O(C1-C6 haloalkyl),—SH, —SR^(o), —NO₂, —CN, —NHCO₂R^(o), —NHC(O)H, —NHC(O)R^(o), —CO₂H,—CO₂R^(o), —C(O)H, —C(O)R^(o), —C(O)NHR^(o), —OC(O)R^(o), —S(O)₂R^(o),—SO₂NH₂, —S(O)R^(o), —NHSO₂R^(o), —N(R^(o))₂, —NR^(o)C(O)R^(o),—C(O)N(R^(o))₂ or a C1-C6 alkyl group substituted with R^(o), —OH,—OR^(o), —SH, —SR^(o), —NO₂, —CN, —NHCO₂R^(o), —NHC(O)H, —NHC(O)R^(o),—CO₂H, —CO₂R^(o), —C(O)H, —C(O)R^(o), —C(O)NHR^(o), —OC(O)R^(o),—S(O)₂R^(o), —SO₂NH₂, —S(O)R^(o) or —NHSO₂R^(o); R^(o) is independentlyC1-C6 alkyl, aryl or heteroaryl group and wherein the aryl or heteroarylgroup represented by R^(o) is optionally substituted with one or morehalogen, methyl or methoxy groups.
 13. The composition of claim 12wherein the compound is represented by Formula (III):


14. The composition of claim 13 wherein the compound is represented byFormula (IV):

wherein one of B₁ through B₃ and one of D₁ through D₃ are N.
 15. Thecomposition of claim 14 wherein R₁ is —H or a C1-C3 alkyl optionallysubstituted with a halogen or a hydroxyl.
 16. The composition of claim15 wherein R^(c) is —H, halogen, —NO₂, —CN, C1-C3 alkyl, C1-C3haloalkyl, C1-C3 hydroxyalkyl or C1-C3 alkoxyalkyl, —N(R^(d))₂,—NR^(d)C(O)R^(d), or —C(O)N(R^(d))₂; and each R^(d) is H or a C1-C3alkyl group.
 17. The composition of claim 16 wherein the compound isselected from the group consisting of:

wherein R′ and R″ are independently —H, halogen, —NO₂, —CN, C1-C3 alkyl,C1-C3 haloalkyl, C1-C3 hydroxyalkyl, C1-C3 alkoxyalkyl, —N(R^(d))₂,—NR^(d)C(O)R^(d), or —C(O)N(R^(d))₂.
 18. The composition of claim 17wherein the compound is selected from the group consisting of:


19. The composition of claim 18 wherein the compound is represented byFormula (VId):


20. The composition of claim 18 wherein the compound is represented by(VIf):